Discontinuation of Urate-Lowering Drugs: a Systematic Review Protocol

Discontinuation of urate-lowering drugs: a systematic review protocol

Virginie Beslon, Perrine Moreau, Annabel Maruani, Hubert Maisonneuve, Bruno Giraudeau, Jean-Pascal Fournier

ADMINISTRATIVE INFORMATION Registration PROSPERO registration number:

Review team Virginie Beslon, Département de médecine générale, Université de Nantes, France ; [email protected] Perrine Moreau, Département de médecine générale, Université de Nantes, France ; [email protected] Annabel Maruani, Services de dermatologie, CHRU de Tours, Université François Rabelais, Tours, France ; [email protected] Hubert Maisonneuve, Unité des Internistes Généralistes et Pédiatres, Faculté de Médecine, Université de Genève, Suisse ; [email protected] Bruno Giraudeau, INSERM CIC 1415, CHRU de Tours, Université François-Rabelais, Tours, France ; [email protected] Jean-Pascal Fournier, Département de médecine générale, EA 4275-SPHERE, Université de Nantes, France ; [email protected]

Contact details Jean-Pascal Fournier (guarantor) Département de médecine générale, Université de Nantes EA 4275-SPHERE, Biostatistique, Recherche Clinique et Mesures Subjectives en Santé, Université de Nantes 1 rue, Gaston Veil, 44000, Nantes, France [email protected]

Contributions 1. Draft the protocol: VB, PM, AM, HM, BG, JPF 2. Study selection: VB, PM, JPF 3. Extract data from studies: VB, PM, JPF 4. Carry out the analysis: VB, PM, JPF 5. Interpret the analysis: VB, PM, AM, HM, BG, JPF 6. Draft the final review: VB, PM, JPF 7. Critical revision of the review for important intellectual content: VB, PM, AM, HM, BG, JPF

Anticipated or actual start date December 30, 2015

Anticipated completion date October 30, 2016

Dissemination plans This paper will be submitted to a leading journal in this field. We can also use this paper for oral or poster presentation in any leading conference at national or international level.

Funding sources/sponsors None

Conflicts of interest The authors have no conflict of interest to report. INTRODUCTION Rationale Gout is an urate crystal deposition disease and the most common rheumatic disease in adults (0.9% of adults in France and 3.9 % in the US) (1,2). In the last decade the prevalence of gout has raised worldwide, related with the increase in age of population, obesity, and alcohol consumption (3).

Urate-lowering therapy is recommended in case of symptomatic hyperuricemia (acute gouty arthritis, tophi, urate nephropathy, and uric acid nephrolithiasis) and can be used prophylactically to prevent chemotherapy-induced hyperuricemia. Allopurinol is the most commonly used urate- lowering drug, and acts through inhibition of xanthine oxidase. Other urate-lowering drugs include febuxostat, probenecid, sulfinpyrazone, benzbromarone. These drugs aim at reducing acid uric level below 360 mmol/L (6.0 mg/ddL) (4). Urate-lowering drugs are also widely used off-label for treating asymptomatic hyperuricemia (50% to 56.8% of patients with allopurinol in France) (5–7).

According to experts, urate-lowering drugs should be used in the long-term, and even indefinitely. However, compliance to urate-lowering drugs is poor in practice (8,9). High spontaneous withdrawal rates motivate the global assessment of the effects of discontinuing these drugs.

Objectives The overall purpose of this systematic review is to evaluate the recurrence of gouty arthritis, tophi, urate nephropathy, or uric acid nephrolithiasis after discontinuation of urate-lowering drug, and time to clinical effects. Secondary aims include the assessment of adverse events and urate-lowering drugs reintroduction rates.

METHODS Eligibility criteria We will include all types of studies [all randomized control trials (RCTs), clinical control trials (CCTs) and observational studies (case control, longitudinal study)], investigating the effect of discontinuation of urate-lowering drugs in adults (18 years of age and over). We will include studies assessing discontinuation of any urate-lowering drug: xanthine oxidase inhibitor drug (allopurinol, febuxostat) or conventional uricosuric drug (probenecid, sulfinpyrazone, benzbromarone). Studies assessing switches between urate-lowering drugs will not be included. Studies assessing short-term effects (less than 3 months) of urate-lowering drugs will not be included.

Studies will be included regardless of the urate-lowering drug indication (acute gouty arthritis, tophi, urate nephropathy, uric acid nephrolithiasis, prophylaxis of chemotherapy-induced hyperuricemia, asymptomatic hyperuricemia, other). If the same participants are assessed in different time points or in multiple studies, we will extract and analyze all the data of different follow-up periods, and choose those with the longest follow-up for analysis. The search will be limited by language (English, French, and Spanish), and only studies including human subjects will be included.

Information sources We will search the following databases from inception to current date: The Cochrane Central Register of Controlled Trials (CENTRAL), via the Cochrane Library, Wiley InterScience (www.thecochranelibrary.com), MEDLINE, EMBASE, Science Citation Index (web of science), and ClinicalTrials.gov (www.ClinicalTrials.gov).

We will also perform hand search articles from reference lists of articles. We will also perform manual hand search through conference abstracts of the American College of Rheumatology/The Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meetings (2006-2015) and European League Against Rheumatism (EULAR) Annual Congresses (2002-2015).

Search strategy The following search strategy for MEDLINE has been developed in collaboration with a librarian:

Allopurinol [All Fields] OR febuxostat [All Fields] OR probenecid [All Fields] OR benzbromarone [All Fields] OR urate lowering [All Fields] OR xanthine oxidase inhibitor [All Fields] OR antihyperuricemic [All Fields] OR anti-hyperuricemic [All Fields] OR gout suppressants [All Fields] AND stop* OR withdr* [All Fields] OR cess* [All Fields] OR ceas* [All Fields] OR discontinu*[All Fields] OR withhold* [All Fields] OR step-down [All Fields] OR deprescri* [All Fields] OR taper* [All Fields] OR halt* [All Fields] OR drop-out [All Fields] [All Fields] NOT (animals [Mesh] NOT humans [Mesh])

Subsequent search strategies will be derived from the MEDLINE strategy and adapted for each database.

Study records - Data management and selection process Three reviewers [VB, PM and JPF] will independently screen the titles and abstracts for inclusion of all the potential studies using Abstarckr. Any discrepancies will be discussed and resolved by consensus. Full copies of all studies deemed potentially relevant will be obtained and the same three reviewers [VB, PM and JPF] will independently assess these for inclusion; any disagreements will be resolved by consensus. We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram.

- Data collection process Two review authors (VB and PM) will extract data independently; discrepancies will be identified and resolved by consulting the third author (JPF). A standardized, pre-piloted form will be used to extract data from the included studies, for assessment of study quality and evidence synthesis.

Data items Extracted information will include: 1. Methods: study design, total duration of study, number of study centers and location, study setting, follow-up duration after ULT discontinuation, and date of study. 2. Participants: N, mean age, age range, sex, disease duration, severity of condition, diagnostic criteria, duration of urate-lowering drug treatment before discontinuation; inclusion criteria, and exclusion criteria. 3. Interventions: type of discontinuation (abrupt, titration), comparison (if applicable), concomitant medications, excluded medications. 4. Outcomes: recurrence of gouty arthritis, tophi, urate nephropathy, or uric acid nephrolithiasis adverse events, urate-lowering drugs reintroduction, serum urate level, time of measurement. 5. Notes: funding for trial, and notable declarations of interest of trial authors.

Risk of bias in individual studies Two review authors (VB and PM) will independently assess risk of bias for each study. We will resolve any disagreements by discussion or by involving another author (JPF). We will use the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials for the RCT and the ACROBAT-NSRI tool for the non-randomized studies. In case of non-comparative studies, the first 8 items of the MINORS checklist will be used to assess the quality of included studies.

Data synthesis After extracting data from each study, we will insert the obtained data into structured tables. We will provide a narrative synthesis of the findings from the included studies, structured around the type of intervention, population characteristics, and type of outcomes. We anticipate that there will be limited scope for meta-analysis because of the range of different outcomes measured across the small number of existing studies.

Additional analyses We plan to carry out the following subgroup analyses if available data is sufficient: 1. Age group 2. Indication of urate-lowering drug 3. Duration of urate-lowering treatment at baseline 4. Type of urate-lowering drug 5. Dose of urate-lowering drug

Meta-biases If possible, funnel plots will be used.

Confidence in cumulative evidence Quality of evidence will be assessed using the GRADE approach, if possible.

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